Replicative capacity of SARS-CoV-2 omicron variants BA.5 and BQ.1.1 at elevated temperatures
Authors: Yukiko Muramoto, Senye Takahashi, Peter J Halfmann, Shimpei Gotoh, Takeshi Noda, Yoshihiro Kawaoka
Journal: The Lancet Microbe (2023)

After the SARS-CoV-2 omicron variants replaced the delta variant (B.1.617.2), omicron subvariants, including BQ.1.1 and XBB, emerged and became the dominant strain worldwide. Although the omicron subvariants are more immunoevasive than earlier variants,1Imai M Ito M Kiso M et al.Efficacy of antiviral agents against omicron subvariants BQ.1.1 and XBB.N Engl J Med. 2023; 388: 89-91Crossref PubMed Scopus (74) Google Scholar, 2Uraki R Ito M Furusawa Y et al.Humoral immune evasion of the omicron subvariants BQ.1.1 and XBB.Lancet Infect Dis. 2023; 23: 30-32Summary Full Text Full Text PDF PubMed Scopus (50) Google Scholar their virological characteristics, such as replicative capacity in respiratory organs during pyrexia,3Herder V Dee K Wojtus JK et al.Elevated temperature inhibits SARS-CoV-2 replication in respiratory epithelium independently of IFN-mediated innate immune defenses.PLoS Biol. 2021; 19e3001065 Crossref Scopus (12) Google Scholar are not fully understood. We compared the replicative capacity of B.1.617.2, BA.5, and BQ.1.1 during pyrexia by using human alveolar epithelial cells (AECs) in an air–liquid interface culture, which were generated from induced pluripotent stem cells. Human AECs were infected with 1 × 104 50% tissue culture infectious dose (TCID50) of B.1.617.2, BA.5, and BQ.1.1, and incubated at two different temperatures, 37°C (normal human body temperature) and 40°C (elevated human body temperature during illness). Samples were collected daily from the apical surface of the AECs up to 4 days post infection (dpi) for viral titration. All three variants had similar growth kinetics on human AECs at 37°C, reaching peak titres of 107·5–108·5 TCID50/mL at 2 dpi (appendix p 2). Notably, although the viral titres of B.1.617.2 at 2 dpi were 10 times lower at 40°C (106·5 TCID50/mL) than at 37°C (108·2 TCID50/mL), viral titres of BA.5 were 1000 times lower at 40°C (104·6 TCID50/mL) than at 37°C (107·5 TCID50/mL), and BQ.1.1 was unable to replicate at the higher temperature in human AECs (appendix p 2). In Vero E6 cells expressing TMPRSS2 (VeroE6/TMPRSS2), the three SARS-CoV-2 variants had similar replication kinetics at 37°C to those in human AECs at the same temperature, with peak titres at 2 dpi (appendix p 1). Virus-infected VeroE6/TMPRSS2 cells grown at 37°C were dead by 3 dpi due to virus growth. At 40°C in VeroE6/TMPRSS2 cells, the titre of B.1.617.2 was again 10 times lower than that at 37°C (appendix p 1). The virus titres for BA.5 and BQ.1.1 were also substantially reduced at 40°C compared with titres at 37°C, showing that the replicative capacities of BA.5 and BQ.1.1 were restricted at the higher temperature. Our data show that omicron variants—especially BQ.1.1—cannot replicate efficiently at high temperatures, unlike B.1.617.2. Because pyrexia is one of the most common symptoms in patients with SARS-CoV-2 infection (including the omicron variant), elevated body temperature during the illness might substantially restrict BA.5 and BQ.1.1 replication in the lungs and could have an important role in limiting disease severity caused by the omicron variants. Thus, BA.5 and BQ.1.1 show lower pathogenicity than B.1.617.2. Further study is needed to reveal the determinants responsible for the temperature sensitivity of SARS-CoV-2 variants, which could lead to a better understanding of viral pathogenesis. YM designed and did infection experiments and data analysis. ST and SG generated human AECs derived from induced pluripotent stem cells. PJH, TN, and YK obtained funding, conceived the study, and wrote the draft, with all other authors providing editorial comments. YK is supported by grants from the Center for Research on Influenza Pathogenesis (HHSN272201400008C) and from the Center for Research on Influenza Pathogenesis and Transmission (75N93021C00014), funded by the National Institute of Allergy and Infectious Disease; by a Research Program on Emerging and Reemerging Infectious Diseases (JP21fk0108552 and JP21fk0108615), a Project Promoting Support for Drug Discovery (JP21nf0101632), the Japan Program for Infectious Diseases Research and Infrastructure (JP22wm0125002), and a grant (JP223fa627001) from the Japan Agency for Medical Research and Development; and has received unrelated funding support from Daiichi Sankyo Pharmaceutical, Toyama Chemical, Tauns Laboratories, Shionogi, Otsuka Pharmaceutical, KM Biologics, Kyoritsu Seiyaku, Shinya Corporation, and Fuji Rebio. TN is supported by the JST Core Research for Evolutional Science and Technology (JPMJCR20HA), the JSPS Core-to-Core Program A (JPJSCCA20190008), the Kansai Economic Federation (KANKEIREN), the Joint Research Project of the Institute of Medical Science at the University of Tokyo, and the Joint Usage/Research Center Program of the Institute for Life and Medical Sciences at Kyoto University. SG is supported by the Fight Corona Project funded by the COVID-19 Private Fund (to Shinya Yamanaka, CiRA, Kyoto University), has received unrelated funding support from Kyorin Pharmaceutical, and is a founder and shareholder of HiLung. All other authors declare no competing interests. We thank Susan Watson for scientific editing. We also thank Chiho Onishi, Koichi Igura, and Naoyuki Sone for technical assistance. Download .pdf (.57 MB) Help with pdf files Supplementary appendix